Nothing Special   »   [go: up one dir, main page]

EP0863868A1 - Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives - Google Patents

Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives

Info

Publication number
EP0863868A1
EP0863868A1 EP96941602A EP96941602A EP0863868A1 EP 0863868 A1 EP0863868 A1 EP 0863868A1 EP 96941602 A EP96941602 A EP 96941602A EP 96941602 A EP96941602 A EP 96941602A EP 0863868 A1 EP0863868 A1 EP 0863868A1
Authority
EP
European Patent Office
Prior art keywords
formula
dimethyl sulphoxide
carbon atoms
compound
temperature
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP96941602A
Other languages
German (de)
French (fr)
Other versions
EP0863868B1 (en
Inventor
Stephen John Barker
Sharon Michelle Clark
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Priority to SI9630254T priority Critical patent/SI0863868T1/en
Publication of EP0863868A1 publication Critical patent/EP0863868A1/en
Application granted granted Critical
Publication of EP0863868B1 publication Critical patent/EP0863868B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the present invention relates to an improved process for the preparation of arylcyclobutyl cyanides.
  • 1-(4-Chlorophenyl)cyclobutyl cyanide is an intermediate useful for the preparation of sibutramine, N-1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutyl-N,N-dimethylamine.
  • Sibutramine is useful in the treatment of depression, Parkinson's disease, obesity, Non Insulin Dependent Diabetes Mellitus (NIDDM) and epilepsy.
  • 1-(4-Chlorophenyl)cyclobutyl cyanide was prepared by reacting 4- chlorophenylacetonitrile with 1 ,3-dibromobutane in a mixture of dimethyl sulphoxide and ether at 25-35°C using sodium hydride as the base (J.Org. Chem. 36 (9), 1308, 1971). It is also disclosed that the process is effective if the mineral oil is removed from the sodium hydride by washing with toluene and then adding a slurry of sodium hydride in toluene to the dimethyl sulphoxide. Similar preparations are also described in US4.235.926, US3.526.656. US4.348.409, US5,405,866 and J.Organomet. Chem. 448, 1-2, p9-14(1993). The yields quoted vary between 43% and 78%.
  • GB2098602A discloses a process for the preparation of 1-(4- chlorophenyl)cyclobutyl cyanide comprising the reaction of 4-chlorophenyl- acetonitrile with a 1 ,3-dibromopropane in the presence of sodium hydride (dispersed in mineral oil). The reaction is described as being carried out in dry dimethyl sulphoxid ⁇ under nitrogen with stirring initially at room temperature, then at a temperature in the range 30 to 35°C for 2 hours. This preparation is also reported in EP 191542 and GB 2127819. The presence of dimethyl sulphoxide in the aqueous waste from these processes renders the waste ineligible for discharge to the chemical effluent drain of chemical production plants. The waste therefore has to be specially disposed of. This leads to high production costs and adverse environmental effects (more resources and energy are required to enable safe disposal of the aqueous waste). It is therefore desirable to find a process which does not require dimethyl sulphoxide.
  • WO95/00489 describes a process for producing 1-(2-pyridyl)cyclopropyl cyanide This reaction was carried out in toluene using a 50% aqueous sodium hydroxide solution as the base. The base was added to a stirred mixture of 2-(2- pyridyl)acetonitrile, l-bromo-2-chloroethane, benzyltriethylammonium chloride and toluene at 25°C. The mixture was then heated at 70-75°C for 2 hours. The product was extracted into ether and isolated in good yield (-85%). A disadvantage of this process is the presence of water in the initial reaction. This can lead to a rather high level of impurity formation.
  • the present invention provides a process for the preparation of compounds of formula I
  • R, and R 2 which may be the same or different, are H, halo, trifluoromethyl, an alkyl group containing 1 to 3 carbon atoms, an alkoxy or alkylthio group containing 1 to 3 carbon atoms, phenyl, or R, and R 2 , together with the carbon atoms to which they are attached, form a second benzene ring which may be substituted by one or more substituents selected from halo, an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, or the substituents of the second benzene ring together with the two carbon atoms to which they are attached may form a further benzene ring;
  • said process comprising the reaction of a 1 ,3-dihalopropane, a compound of formula " in which RT and R 2 are as defined above, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • a preferred process according to the present invention provides a process for the preparation of compounds of formula I as defined by formula III
  • R 1 and R 2 are as defined above, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a termperature of at least 35°C.
  • a more preferred process according to the present invention provides a process for the preparation of compounds of formula IV in which Ri represents chloro and R 2 represents hydrogen or chloro comprising the reaction of a 1,3- dihalopropane, a compound of formula IV in which R 1 represents chloro and R 2 represents hydrogen or chloro, respectively, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • the more preferred processes of the present invention provide a) a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of a 1 ,3-dihalopropane, 4-chlorophenylacetonitrile and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C; and b) a process for the preparation of 1-(3,4-dichlorophenyl)cyclobutyl cyanide and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • a most preferred process of the present invention provides a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of a 1 ,3- dihalopropane, 4-chlorophenylacetonitrile and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • the process comprises the addition of a solution of a 1,3- dihalopropane and a compound of formula II in a substantially dimethyl sulphoxide- free solvent to a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • solvent defines a water-immiscible liquid which is capable of keeping the 1 ,3-dihalopropane and the 4-chlorophenylacetonitrile in solution at the reaction temperature.
  • the use of a water-immisicible liquid is advantageous as the work-up procedure is simplified and therefore process costs are reduced.
  • substantially dimethyl sulphoxide-free means that no more than 5% of dimethyl sulphoxide is present in the solvent, preferably no more than 2%, and most preferably there is a complete absence of dimethyl sulphoxide.
  • the dimethyl sulphoxide-free solvent is a water immiscible organic liquid, preferably the liquid is non-polar. More preferably, the dimethyl sulphoxide- free solvent is a hydrocarbon such as toluene or petroleum ether. Most preferably the dimethyl sulphoxide-free solvent is toluene.
  • the base is potassium hydroxide or sodium hydroxide.
  • the amount of base present is at least 2 molar equivalents relative to the amount of the compound of formula II present. More preferably, the amount is in the range of 3.8 to 4.7 molar equivalents relative to the amount of the compound of formula II present.
  • the suspension of base is preferably maintained by agitation such as stirring, shaking, or bubbling an inert gas, such as nitrogen, through the solvent, but any other means of maintaining a suspension may also be used.
  • agitation such as stirring, shaking, or bubbling an inert gas, such as nitrogen, through the solvent, but any other means of maintaining a suspension may also be used.
  • an inert gas such as nitrogen
  • it is a stirred suspension.
  • reaction is carried out under an inert atmosphere such as nitrogen.
  • phase-transfer catalyst present in the suspension of the base.
  • the phase transfer catalyst is a quaternary salt or a crown ether.
  • the catalyst is selected from one of the following: butylpyridinium bromide, tetrabutylammonium bisulphate, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylamrnonium fluoride, hexadecyltriethylammonium bromide, hexadecyltriethylphosphonium bromide, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, dibutyldimethylammonium chloride, decyltriethylammonium bromide, hexadecyttributylphosphon
  • phase transfer catalyst is a quaternary ammonium salt or a crown ether.
  • phase-transfer catalyst is tetra-n-butylammonium bromide, tetra-n- butylammonium hydrogen sulphate, or tetra-n-butylammonium iodide.
  • the amount of phase-transer catalyst present is in the range of 0.01 to 0.2 molar equivalents relative to the amount of the compound of formula II present. More preferably the amount is in the range of 0.05 to 0.15 molar equivalents relative to the amount of the compound of formula II present.
  • the temperature is in the range 35-80°C, more preferably in the range 35.1-69°C, most preferably in the range 40-60°C.
  • water is added to aid stirring when the addition is 60-85% complete, more preferably 75% complete.
  • the volume of water added is in the range of 0 to 5.0 parts by weight relative to the weight of the compound of formula II present.
  • the volume of water added is in the range of 0 to 1.0 parts of weight relative to the weight of the compound of formula II present. More preferably the volume of water added is on the range of 0.7 to 0.9 parts by weight relative to the weight of the compound of formula II present.
  • the reaction is quenched by the addition of water.
  • the reaction is carried out at atmospheric pressure.
  • the 1 ,3-dihalopropane is 1 ,3-dibromopropane, 1 ,3-dichloropropane or 1-bromo-3-chloropropane.
  • the 1 ,3-dihalopropane is 1 ,3- dibromopropane.
  • the amount of 1 ,3-dihalopropane used is in the range of 0.8 to 1.5 molar equivalents relative to the amount of the compound of formula II present.
  • the amount of 1 ,3-dihalopropane used is in the range of 0.9 to 1.2 molar equivalents relative to the amount of the compound of formula II present.
  • the amount of 1 ,3-dihalopropane used is in the range .0 to 1.05 molar equivalents relative to the amount of the compound of formula II present.
  • a further advantage of the present invention is that it may avoid the need for isolation of 1-(4-chlorophenyl)cyclobutyl cyanide when it is desired to obtain sibutramine. Instead it may be possible to use the toluene solution of 1-(4- chlorophenyl)cyclobutanecarbonitrile immediately in the reaction described in GB2098602A, inco ⁇ orated herein by reference.
  • the process comprises the addition of a solution of 1 ,3-dibromopropane and 4-chlorophenylacetonitrile in toluene to a stirred suspension of powdered potassium hydroxide with tetra-n- butylammonium bromide in toluene at a temperature in the range 35-80°C, preferably in the range 35.1 -69°C, more preferably in the range 40-60°C. Water is added after 60-85% completion of the addition. The reaction is quenched by the addition of water.
  • the invention is illustrated by the following Examples which are given by way of example only.
  • the final product of each of these Examples was characterised by one or more of the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
  • the organic phase was separated and stirred with water (354 ml) and caustic soda (76 g) at f°C for 15 minutes, then allowed to settle.
  • the organic layer was separated, then stirred at f°C with water (300 ml) and concentrated hydrochloric acid (20 ml), the aqueous layer having a pH of 3 or less.
  • the organic layer was separated, then stirred with water (300 ml) at f°C for 15 minutes and the organic layer separated. This was repeated until the aqueous layer had a pH between 6 and 8.
  • TBAHS tetra-n-butylammonium hydrogen sulphate.
  • Temperatures d°C and f°C are the same for Examples 1-10.
  • TBAHS tetra-n-butylammonium hydrogen sulphate
  • TBAB means tetra-n-butylammonium bromide
  • TBAHS means tetra-n-butylammonium hydrogen sulphate
  • DMSO means dimethyl sulphoxide
  • the reaction is then quenched by addition of water (254 ml) over 15 minutes at 60°C, and the mixture stirred for 20 minutes.
  • the organic phase is separated and stirred with water (354 ml) and caustic soda (76 g) at 60°C for 15 minutes, then allowed to settle.
  • the organic layer is separated, then stirred at 60°C with water (300 ml) and concentrated hydrochloric acid (20 ml), the aqueous layer having a pH of 3 or less.
  • the organic layer is separated, then stirred with water (300 ml) at 60°C for 15 minutes and the organic layer separated. This is repeated until the aqueous layer has a pH between 6 and 8.
  • the solvent is removed in vacuo at 90°C, and the residual oil is distilled at 1.33 to 2.66 mbar under high vacuum to yield in the appropriate fractions of 1-(3,4- dichlorophenyl)cyclobutyl cyanide.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Catalysts (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)

Abstract

A process for the preparation of arylcyclobutylnitrile derivatives which involves reaction of a solution of a 1,3-dihalopropane and a cyanobenzyl derivative in a substantially dimethyl sulphoxide-free solvent with a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35 °C.

Description

PROCESS FOR THE PREPARATION OF 1 -ARYL-1 -CYAN0CYCL0BUTANE DERIVATIVES
The present invention relates to an improved process for the preparation of arylcyclobutyl cyanides. 1-(4-Chlorophenyl)cyclobutyl cyanide is an intermediate useful for the preparation of sibutramine, N-1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutyl-N,N-dimethylamine. Sibutramine is useful in the treatment of depression, Parkinson's disease, obesity, Non Insulin Dependent Diabetes Mellitus (NIDDM) and epilepsy.
The reaction of phenylacetonitrile with a 1 ,3-dihalopropane in aqueous sodium hydroxide using benzyltriethylammonium chloride as a catalyst to give 1- phenylcyclobutyl cyanide is reported in Rocz. Chem. 40, 1647, (1966). However, the yield is low (26%) and the amount of monoalkylated uncyclised product formed is significant (20%).
1-(4-Chlorophenyl)cyclobutyl cyanide was prepared by reacting 4- chlorophenylacetonitrile with 1 ,3-dibromobutane in a mixture of dimethyl sulphoxide and ether at 25-35°C using sodium hydride as the base (J.Org. Chem. 36 (9), 1308, 1971). It is also disclosed that the process is effective if the mineral oil is removed from the sodium hydride by washing with toluene and then adding a slurry of sodium hydride in toluene to the dimethyl sulphoxide. Similar preparations are also described in US4.235.926, US3.526.656. US4.348.409, US5,405,866 and J.Organomet. Chem. 448, 1-2, p9-14(1993). The yields quoted vary between 43% and 78%.
GB2098602A discloses a process for the preparation of 1-(4- chlorophenyl)cyclobutyl cyanide comprising the reaction of 4-chlorophenyl- acetonitrile with a 1 ,3-dibromopropane in the presence of sodium hydride (dispersed in mineral oil). The reaction is described as being carried out in dry dimethyl sulphoxidθ under nitrogen with stirring initially at room temperature, then at a temperature in the range 30 to 35°C for 2 hours. This preparation is also reported in EP 191542 and GB 2127819. The presence of dimethyl sulphoxide in the aqueous waste from these processes renders the waste ineligible for discharge to the chemical effluent drain of chemical production plants. The waste therefore has to be specially disposed of. This leads to high production costs and adverse environmental effects (more resources and energy are required to enable safe disposal of the aqueous waste). It is therefore desirable to find a process which does not require dimethyl sulphoxide.
Initially the reaction was attempted using toluene as the solvent. However, this course of action results in a new problem in that it leads to generation of a significant, delayed exotherm during addition to the reaction mixture of the arylacetonitrile. Such a process is not considered safe. The problem of exotherm generation does not arise when dimethyl sulphoxide is replaced with other water- miscible solvents, such as tetrahydrofuran. However, there is a significant loss of yield which can only be improved by partial distillation of the tetrahydrofuran and addition of a water-immiscible solvent, such as toluene, prior to extraction. Such a procedure has the disadvantages of requiring extra processing (increasing the cost) and of creating a tetrahydrofuran toluene waste stream, both of which render it unsatisfactory. A similar process is described in WO93/13073 (page 180, Example N10) for producing 1 -(4-trif luoromethoxyphenyl)cyclobutyl cyanide. In this process two water-miscible solvents, tetrahydrofuran and dimethylformamide, are used during the reaction, with the water-immiscible solvent ether being used for extraction of the product, to obtain a 61% yield. Again this has the disadvantage of requiring extra processing and producing a tetrahydrof uran/ether waste stream.
WO95/00489 describes a process for producing 1-(2-pyridyl)cyclopropyl cyanide This reaction was carried out in toluene using a 50% aqueous sodium hydroxide solution as the base. The base was added to a stirred mixture of 2-(2- pyridyl)acetonitrile, l-bromo-2-chloroethane, benzyltriethylammonium chloride and toluene at 25°C. The mixture was then heated at 70-75°C for 2 hours. The product was extracted into ether and isolated in good yield (-85%). A disadvantage of this process is the presence of water in the initial reaction. This can lead to a rather high level of impurity formation. However, addition of an equivalent amount of a solid base at 25°C (without the presence of water) would result in a significant delayed exotherm making such a reaction unsafe. Furthermore, it is well known that cyclobutyl rings, as described by the present invention, are considerably less facile to make than the cyclopropyl rings described in the above reference. Therefore it would not be expected that the above procedure would produce as good a yield of cyclobutyl material by using 1-bromo-2-chloropropane instead of 1-bromo-2- chloroethane. Additionally problems can arise from emulsion formation when water is present initially. This may lead to lower yields.
Surprisingly, we have found a process for the preparation of arylcyclobutyl cyanides whereby dimethyl sulphoxide can be excluded, delayed exotherms and mixed solvent waste streams avoided, and impurity formation kept to a minimum whilst still giving the desired product in good yield.
The present invention provides a process for the preparation of compounds of formula I
in which R, and R2, which may be the same or different, are H, halo, trifluoromethyl, an alkyl group containing 1 to 3 carbon atoms, an alkoxy or alkylthio group containing 1 to 3 carbon atoms, phenyl, or R, and R2, together with the carbon atoms to which they are attached, form a second benzene ring which may be substituted by one or more substituents selected from halo, an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, or the substituents of the second benzene ring together with the two carbon atoms to which they are attached may form a further benzene ring;
said process comprising the reaction of a 1 ,3-dihalopropane, a compound of formula " in which RT and R2 are as defined above, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
A preferred process according to the present invention provides a process for the preparation of compounds of formula I as defined by formula III
in which R^ represents halo and R2 represents hydrogen or halo; comprising the reaction of a 1 ,3-dihalopropane, a compound of formula II as defined by formula IV
in which R1 and R2 are as defined above, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a termperature of at least 35°C.
A more preferred process according to the present invention provides a process for the preparation of compounds of formula IV in which Ri represents chloro and R2 represents hydrogen or chloro comprising the reaction of a 1,3- dihalopropane, a compound of formula IV in which R1 represents chloro and R2 represents hydrogen or chloro, respectively, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
The more preferred processes of the present invention provide a) a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of a 1 ,3-dihalopropane, 4-chlorophenylacetonitrile and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C; and b) a process for the preparation of 1-(3,4-dichlorophenyl)cyclobutyl cyanide and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
A most preferred process of the present invention provides a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of a 1 ,3- dihalopropane, 4-chlorophenylacetonitrile and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
Preferably the process comprises the addition of a solution of a 1,3- dihalopropane and a compound of formula II in a substantially dimethyl sulphoxide- free solvent to a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
The term "solvent" defines a water-immiscible liquid which is capable of keeping the 1 ,3-dihalopropane and the 4-chlorophenylacetonitrile in solution at the reaction temperature. The use of a water-immisicible liquid is advantageous as the work-up procedure is simplified and therefore process costs are reduced.
The term "substantially dimethyl sulphoxide-free" means that no more than 5% of dimethyl sulphoxide is present in the solvent, preferably no more than 2%, and most preferably there is a complete absence of dimethyl sulphoxide.
Suitably.the dimethyl sulphoxide-free solvent is a water immiscible organic liquid, preferably the liquid is non-polar. More preferably, the dimethyl sulphoxide- free solvent is a hydrocarbon such as toluene or petroleum ether. Most preferably the dimethyl sulphoxide-free solvent is toluene.
Preferably, the base is potassium hydroxide or sodium hydroxide. Preferably the amount of base present is at least 2 molar equivalents relative to the amount of the compound of formula II present. More preferably, the amount is in the range of 3.8 to 4.7 molar equivalents relative to the amount of the compound of formula II present.
The suspension of base is preferably maintained by agitation such as stirring, shaking, or bubbling an inert gas, such as nitrogen, through the solvent, but any other means of maintaining a suspension may also be used. Preferably it is a stirred suspension.
Preferably the reaction is carried out under an inert atmosphere such as nitrogen.
Preferably, there is a phase-transfer catalyst present in the suspension of the base. Suitably the phase transfer catalyst is a quaternary salt or a crown ether. Preferably the catalyst is selected from one of the following: butylpyridinium bromide, tetrabutylammonium bisulphate, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylamrnonium fluoride, hexadecyltriethylammonium bromide, hexadecyltriethylphosphonium bromide, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, dibutyldimethylammonium chloride, decyltriethylammonium bromide, hexadecyttributylphosphonium bromide, heptylpyridinium bromide, hexadecyltributylphosphonium chloride, hexyltriethylammonium bromide, dodecylpyridinium bromide, dodecyltriethylammonium bromide, methyltrinonylammonium chloride, methyltriphenylammonium bromide, tetrabutylammonium bromide or bisulphate, tetrabutylammonium chloride, tetrabutylammonium cyanide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylphosphonium chloride, tricaprylylmethylammonium chloride, tetraethylammonium chloride, tetramethylammonium bromide, trioctylethylphosphonium bromide, trioctylmethylammonium chloride, trioctylpropylammonium chloride, tetrapropylammonium bromide, tetraphenylarsonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, benzyltrimethylammonium hydroxide, 18-crown-6, dibenzo-18-crown-6, dicyclohexyl-18-crown-6 or mixtures thereof. More preferably the phase transfer catalyst is a quaternary ammonium salt or a crown ether. Most preferably, the phase-transfer catalyst is tetra-n-butylammonium bromide, tetra-n- butylammonium hydrogen sulphate, or tetra-n-butylammonium iodide.
Preferably the amount of phase-transer catalyst present is in the range of 0.01 to 0.2 molar equivalents relative to the amount of the compound of formula II present. More preferably the amount is in the range of 0.05 to 0.15 molar equivalents relative to the amount of the compound of formula II present.
Preferably, the temperature is in the range 35-80°C, more preferably in the range 35.1-69°C, most preferably in the range 40-60°C.
Preferably, water is added to aid stirring when the addition is 60-85% complete, more preferably 75% complete. Suitably the volume of water added is in the range of 0 to 5.0 parts by weight relative to the weight of the compound of formula II present. Preferably the volume of water added is in the range of 0 to 1.0 parts of weight relative to the weight of the compound of formula II present. More preferably the volume of water added is on the range of 0.7 to 0.9 parts by weight relative to the weight of the compound of formula II present.
Preferably, the reaction is quenched by the addition of water.
Preferably, the reaction is carried out at atmospheric pressure.
Suitably the 1 ,3-dihalopropane is 1 ,3-dibromopropane, 1 ,3-dichloropropane or 1-bromo-3-chloropropane. Preferably the 1 ,3-dihalopropane is 1 ,3- dibromopropane.
Suitably the amount of 1 ,3-dihalopropane used is in the range of 0.8 to 1.5 molar equivalents relative to the amount of the compound of formula II present. Preferably the amount of 1 ,3-dihalopropane used is in the range of 0.9 to 1.2 molar equivalents relative to the amount of the compound of formula II present. Most preferably the amount of 1 ,3-dihalopropane used is in the range .0 to 1.05 molar equivalents relative to the amount of the compound of formula II present.
When compounds of formula I are prepared by the process which comprises the present invention, there can be observed a significant financial saving both in terms of raw materials and disposal of the aqueous waste when compared to the known process carried out in dimethyl sulphoxide. Also, there is additional benefit to the environment because it obviates the need to dispose of waste dimethyl sulphoxide. In addition certain impurities which arise from the oxidising nature of dimethyl sulphoxide are eliminated leading to simplified work-up procedures and a purer product.
A further advantage of the present invention is that it may avoid the need for isolation of 1-(4-chlorophenyl)cyclobutyl cyanide when it is desired to obtain sibutramine. Instead it may be possible to use the toluene solution of 1-(4- chlorophenyl)cyclobutanecarbonitrile immediately in the reaction described in GB2098602A, incoφorated herein by reference.
In one embodiment of the present invention, the process comprises the addition of a solution of 1 ,3-dibromopropane and 4-chlorophenylacetonitrile in toluene to a stirred suspension of powdered potassium hydroxide with tetra-n- butylammonium bromide in toluene at a temperature in the range 35-80°C, preferably in the range 35.1 -69°C, more preferably in the range 40-60°C. Water is added after 60-85% completion of the addition. The reaction is quenched by the addition of water.
The invention is illustrated by the following Examples which are given by way of example only. The final product of each of these Examples was characterised by one or more of the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
Examples
The following procedure was carried out under the conditions listed in Table 1 to obtain compounds of formula I.
75% of a mixture (m) of 4-chlorophenylacetonitrie (II) (x g) and 1,3- dibromopropane (y g) in toluene (z ml) was added to a stirred mixture of a base (a g) and a catalyst (b g) in toluene (c ml) over 1.5 hours at a temperature of d°C. Water (e ml) was added, keeping the temperature at d°C. The remaining 25% of the mixture (m) was then added over 30 minutes at d°C, and the mixture stirred for 2.5 hours at f°C. The reaction was then quenched by addition of water (254 ml) over 15 minutes at d°C, and the mixture stirred for 20 minutes.
The organic phase was separated and stirred with water (354 ml) and caustic soda (76 g) at f°C for 15 minutes, then allowed to settle. The organic layer was separated, then stirred at f°C with water (300 ml) and concentrated hydrochloric acid (20 ml), the aqueous layer having a pH of 3 or less. The organic layer was separated, then stirred with water (300 ml) at f°C for 15 minutes and the organic layer separated. This was repeated until the aqueous layer had a pH between 6 and 8.
The solvent was removed in vacuo at 90°C, and the residual oil was distilled at 1.33 to 2.66 mbar under high vacuum to yield in the appropriate fractions a compound of formula I, yield g%. Table 1
Examples 1-10
Mass of Mass of Catalyst Mass of Mass of base Temperature Toluene charge Water charged @ Yield compound II dibromo- catalyst (b g) (powdered (d°C) (z ml) (c ml) 75% of addition (g%)
(x g) propane (y potassium and (e ml) g) hydroxide)(a g) (»°C)
75 105 TBAB 11.8 132 40 66 360 60 53.2
75 105 TBAB 11.8 132 40 66 360 60 57.3
75 105 TBAB 11.8 132 40 66 360 60 61.4
75 105 TBAB 11.8 132 40 66 360 0 56.5
75 105 TBAB 11.8 132 60 66 360 60 57.5
75 105 TBAB 11.8 132 60 66 360 60 63.2
75 105 TBAHS 12.4 132 40 66 360 0 57.8
75 105 TBAHS 12.4 132 40 66 360 0 62.6
75 105 TBAHS 12.4 132 60 66 360 60 61.3 I
75 105 TBAHS 12.4 132 60 66 360 60 57.9 |
5 TBAB means tetra-n-butylammonium bromide; TBAHS means tetra-n-butylammonium hydrogen sulphate. Temperatures d°C and f°C are the same for Examples 1-10.
The same procedure was carried out for Comparative Examples 11-15, except that tetrahydrofuran was used in place of toluene. The temperature (d°C) for the initial reaction was the temperature used in the original process with dimethylsulphoxide, yjz room temperature (20-25°C), rising to 30-35°C (f°C) for the final stir (for 1.5 hours not 2.5 hours) and separation steps. The only exception was Example 15 where the separation steps were carried out at 20-25°C (d°C) instead of 30-35°C (f°C). The other conditions and yields for these Examples are listed in Table 2. It can be seen that the yields are inferior to the results obtained using toluene at a temperature of at least 35°C.
The same procedure was carried out for Comparative Examples 16-17, except that a mixture of dimethyl sulphoxide and toluene was used in place of toluene. The temperature (d°C) for the initial reaction was the temperature used in the original process with dimethylsulphoxide, yjz room temperature (20-25°C), rising to 30-35°C (f°C) for the final stir (for 1.5 hours not 2.5 hours) and separation steps. The other conditions and yields for these Examples are listed in Table 3. It can be seen that the yields are comparable to the results obtained using toluene at a temperature of at least 35°C. However, as mentioned previously there is the disadvantage of waste dimethyl sulphoxide.
Table 2
Comparative Examples 11-15
Mass of Mass of Catalyst Mass of Mass of Temperature (d°C, PC) Tetrahydrofuran Water charged @ Yield (g%) compound dibromo- catalyst (b potassium charge (z+c) 75% of addition n (xg) propane (y g) hydroxide (a g) (including all (e ml) g) washes) (ml)
75 105 TBAB 11.8 132 20-25, 30-35 640 60 29.4
75 105 TBAB 11.8 132 20-25, 30-35 640 0 36.4
75 105 TBAB 11.8 132 20-25, 30-35 790 0 20.3
75 105 TBAB 11.8 132 20-25, 30-35 640 0 44.1
75 105 TBAB 11.8 132 20-25, 30-35 840 0 35.3
5 TBAB means tetra-n-butylammonium bromide; TBAHS means tetra-n-butylammonium hydrogen sulphate.
Table 3 Comparative Examples 6-17
Mass of Mass of Catalyst Mass of Mass of Temperature (d°C, f°C) DMSO/toluene Water charged @ Yield (g%) compound dibromo- catalyst (b potassium charge (z+c) 75% of addition ii (x g) propane (y g) hydroxide (a g) (including all (e ml) g) washes) (ml)
150 209.6 TBAB 22.4 264 20-25, 30-35 120/1080 120 62
75 104.8 TBAB 11.2 132 20-25, 30-35 60/345 60 55
10 TBAB means tetra-n-butylammonium bromide; TBAHS means tetra-n-butylammonium hydrogen sulphate; DMSO means dimethyl sulphoxide.
Example 18
75% of a mixture (m) of 1-(3,4-dichlorophenyl)acetonitrile (92.1 g) and 1,3- dibromopropane (105 g) in toluene (66 ml) is added to a stirred mixture of powdered potassium hydroxide (132 g) and tetra-n-butylammonium bromide (11.8 g) in toluene (360 ml) over 1.5 hours at a temperature of 60°C. Water (60 ml) is added, keeping the temperature at 60°C. The remaining 25% of the mixture (m) is then added over 30 minutes at 60°C, and the mixture stirred for 2.5 hours at 60°C. The reaction is then quenched by addition of water (254 ml) over 15 minutes at 60°C, and the mixture stirred for 20 minutes. The organic phase is separated and stirred with water (354 ml) and caustic soda (76 g) at 60°C for 15 minutes, then allowed to settle. The organic layer is separated, then stirred at 60°C with water (300 ml) and concentrated hydrochloric acid (20 ml), the aqueous layer having a pH of 3 or less. The organic layer is separated, then stirred with water (300 ml) at 60°C for 15 minutes and the organic layer separated. This is repeated until the aqueous layer has a pH between 6 and 8. The solvent is removed in vacuo at 90°C, and the residual oil is distilled at 1.33 to 2.66 mbar under high vacuum to yield in the appropriate fractions of 1-(3,4- dichlorophenyl)cyclobutyl cyanide.

Claims

Claims
1 ) A process for the preparation of compounds of formula I
in which R, and R2, which may be the same or different, are H, halo, trifluoromethyl, an alkyl group containing 1 to 3 carbon atoms, an alkoxy or alkylthio group containing 1 to 3 carbon atoms, phenyl, or R, and R2, together with the carbon atoms to which they are attached, form a second benzene ring which may be substituted by one or more substituents selected from halo, an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, or the substituents of the second benzene ring together with the two carbon atoms to which they are attached may form a further benzene ring;
said process comprising the reaction of a 1 ,3-dihalopropane, a compound of formula II
and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
2) A process as claimed in claim 1 comprising the addition of a solution of a 1 ,3- dihalopropane and a compound of formula li in a substantially dimethyl sulphoxide-free solvent to a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
3) A process as claimed in claim 2 in which there is a phase-transfer catalyst present in the suspension of the base.
4) A process as claimed in claim 3 in which the phrase-transfer catalyst is tetra-n- butylammonium bromide, tetra-n-butylammonium hydrogen sulphate, tetra-n- butylammonium iodide or a crown ether. 5) A process as claimed in any preceding claim in which the dimethyl sulphoxide- free solvent is toluene.
6) A process as claimed in any preceding claim in which the base is potassium hydroxide or sodium hydroxide.
7) A process as claimed in any preceding claim in which the temperature is in the range 35-80°C.
8) A process as claimed in any preceding claim in which the compound of formula II is 4-chlorophenylacetonitrile.
9) A process as claimed in any preceding claim in which the compound of formula II is 3,4-dichlorophenylacetonitrile.
10) A process as claimed in claim 2 in which water is added after 60-85% of the addition is complete.
EP96941602A 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives Expired - Lifetime EP0863868B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI9630254T SI0863868T1 (en) 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9524681.5A GB9524681D0 (en) 1995-12-02 1995-12-02 Chemical process
GB9524681 1995-12-02
PCT/EP1996/005246 WO1997020810A1 (en) 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives

Publications (2)

Publication Number Publication Date
EP0863868A1 true EP0863868A1 (en) 1998-09-16
EP0863868B1 EP0863868B1 (en) 2001-02-21

Family

ID=10784817

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96941602A Expired - Lifetime EP0863868B1 (en) 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives

Country Status (28)

Country Link
US (1) US6545173B1 (en)
EP (1) EP0863868B1 (en)
JP (1) JP2000501402A (en)
KR (1) KR19990071838A (en)
CN (1) CN1075057C (en)
AT (1) ATE199247T1 (en)
AU (1) AU717603B2 (en)
BG (1) BG63498B1 (en)
BR (1) BR9611683A (en)
CA (1) CA2235043A1 (en)
CZ (1) CZ164798A3 (en)
DE (1) DE69611835T2 (en)
DK (1) DK0863868T3 (en)
ES (1) ES2154848T3 (en)
GB (1) GB9524681D0 (en)
GR (1) GR3035572T3 (en)
HU (1) HUP9903481A3 (en)
IL (1) IL124341A (en)
MX (1) MX9804022A (en)
NO (1) NO309265B1 (en)
NZ (1) NZ323896A (en)
PL (1) PL185047B1 (en)
PT (1) PT863868E (en)
RU (1) RU2179168C2 (en)
SI (1) SI0863868T1 (en)
SK (1) SK282470B6 (en)
TR (1) TR199800987T2 (en)
WO (1) WO1997020810A1 (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6476078B2 (en) 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6974838B2 (en) 1998-08-24 2005-12-13 Sepracor Inc. Methods of treating or preventing pain using sibutramine metabolites
US6331571B1 (en) 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
US6339106B1 (en) 1999-08-11 2002-01-15 Sepracor, Inc. Methods and compositions for the treatment and prevention of sexual dysfunction
US6399826B1 (en) 1999-08-11 2002-06-04 Sepracor Inc. Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain
US6504044B2 (en) 2001-02-28 2003-01-07 Council Of Scientific And Industrial Research Process for the preparation of 1-[cyano(aryl)methyl] cyclohexanol
EP1238967B1 (en) * 2001-02-28 2005-04-27 Council of Scientific and Industrial Research A process for the preparation of 1-(cyano(aryl)methyl) cyclohexanol
WO2002083631A1 (en) 2001-04-13 2002-10-24 Sepracor Inc. Methods of preparing didesmethylsibutramine and other sibutramine derivatives
AT503354B1 (en) * 2006-02-22 2008-07-15 Dsm Fine Chem Austria Gmbh METHOD FOR THE PRODUCTION OF 3,4-DISUBSTITUTED PHENYL ACETIC ACIDS, AND NEW INTERMEDIATE COMPOUNDS
CZ2008352A3 (en) * 2008-06-09 2009-09-09 Lucební závody Draslovka a. s. Kolín Process for preparing cycloalkanecarbonitrile

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3526656A (en) 1967-05-25 1970-09-01 Parke Davis & Co (1-arylcyclobutyl)carbonyl carbamic acid derivatives
US4220591A (en) 1975-11-26 1980-09-02 Commonwealth Scientific And Industrial Research Organization Insecticidal esters
AU4244478A (en) 1977-12-19 1979-06-28 Commw Scient Ind Res Org Cyclobutane carboxylic acids and esters and insecticides
IE52768B1 (en) 1981-04-06 1988-02-17 Boots Co Ltd 1-arylcyclobutylalkylamine compounds useful as therapeutic agents
ZA821577B (en) * 1981-04-06 1983-03-30 Boots Co Plc Therapeutic agents
ZA925185B (en) 1991-07-18 1993-04-29 Hoffmann La Roche Dithianes.
GB9127306D0 (en) 1991-12-23 1992-02-19 Boots Co Plc Therapeutic agents
GB9309749D0 (en) 1993-05-12 1993-06-23 Boots Co Plc Therapeutic agents
SK280108B6 (en) 1993-06-22 1999-08-06 Knoll Aktiengesellschaft Tetrahydroisoquinoline derivatives, pharmaceutical compositions them containing, preparation and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9720810A1 *

Also Published As

Publication number Publication date
DE69611835D1 (en) 2001-03-29
US6545173B1 (en) 2003-04-08
TR199800987T2 (en) 1998-09-21
EP0863868B1 (en) 2001-02-21
CA2235043A1 (en) 1997-06-12
DE69611835T2 (en) 2001-06-07
SI0863868T1 (en) 2001-06-30
AU717603B2 (en) 2000-03-30
PL326926A1 (en) 1998-11-09
WO1997020810A1 (en) 1997-06-12
ATE199247T1 (en) 2001-03-15
PL185047B1 (en) 2003-02-28
IL124341A0 (en) 1998-12-06
IL124341A (en) 2001-09-13
SK282470B6 (en) 2002-02-05
CZ164798A3 (en) 1998-09-16
MX9804022A (en) 1998-09-30
HUP9903481A1 (en) 2001-01-29
NO982474L (en) 1998-05-29
GB9524681D0 (en) 1996-01-31
DK0863868T3 (en) 2001-03-19
BR9611683A (en) 1999-03-02
BG63498B1 (en) 2002-03-29
ES2154848T3 (en) 2001-04-16
CN1203585A (en) 1998-12-30
NO309265B1 (en) 2001-01-08
GR3035572T3 (en) 2001-06-29
KR19990071838A (en) 1999-09-27
HUP9903481A3 (en) 2001-11-28
JP2000501402A (en) 2000-02-08
RU2179168C2 (en) 2002-02-10
PT863868E (en) 2001-06-29
WO1997020810A8 (en) 2000-10-05
SK62698A3 (en) 1999-02-11
AU1093997A (en) 1997-06-27
NZ323896A (en) 2000-01-28
BG102473A (en) 1999-05-31
CN1075057C (en) 2001-11-21
NO982474D0 (en) 1998-05-29

Similar Documents

Publication Publication Date Title
US6545173B1 (en) Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives
JPH06179661A (en) Preparation of mono- and di-aryl- triazine
US4145364A (en) Preparation of fluorinated anilines
CA2089271C (en) Process for preparing 3-trifluoromethyl benzyl chloride
JPH09176140A (en) Production of 2-chloro-5-chloromethylthiazole
US6407251B1 (en) Process for preparing 2-chloro-5-chloromethylthiazole
JP2009137955A (en) IMPROVED PRODUCTION METHOD OF CYCLOALKYL AND HALOALKYL o-AMINOPHENYL KETONES
MXPA05004234A (en) Process for the preparation of 2,6-dihalo-para-trifluoromethylaniline.
US4221746A (en) Preparation of hexanitrostilbene
JP4169370B2 (en) Process for producing acetophenones having a fluoroalkyl-substituted aromatic nucleus
JP3557624B2 (en) Method for producing 4,6-dinitrohalobenzene
US5872290A (en) Preparation of acid chlorides
US5977370A (en) Process for preparing pyridine chloride
KR910003817B1 (en) Dehydrohalogenation of substituted-halocumene
US6069255A (en) Preparation of vinyl isothiocyanates
US2678319A (en) Preparation of 2,3-dihalotetrahydro-2-methylfurans
JPH06135942A (en) Production of 2-cyano-4,6-dimethoxypyrimidine
JP2001302647A (en) Method for purifying 2-substituted-1,2-benzisothiazol-3- ones
KR920008616B1 (en) Process for preparing heterocyclic holide compound
JP2000239197A (en) Production of ortho-chlorostyrene
JP2001354662A (en) Method for producing 2-cyanopiperazine
JPS62212332A (en) Production of vinylcyclopropane compound
JPH06145149A (en) Production of 5-amino-4-chloro-3-methylpyrazole hydrochloride

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980504

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: LV PAYMENT 980504;RO PAYMENT 980504;SI PAYMENT 980504

17Q First examination report despatched

Effective date: 19990720

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: LV PAYMENT 19980504;RO PAYMENT 19980504;SI PAYMENT 19980504

REF Corresponds to:

Ref document number: 199247

Country of ref document: AT

Date of ref document: 20010315

Kind code of ref document: T

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: SCHMAUDER & PARTNER AG PATENTANWALTSBUERO

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 69611835

Country of ref document: DE

Date of ref document: 20010329

ITF It: translation for a ep patent filed
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2154848

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20010327

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20010919

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20010921

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20010928

Year of fee payment: 6

Ref country code: FI

Payment date: 20010928

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20011004

Year of fee payment: 6

Ref country code: AT

Payment date: 20011004

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20011019

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20011025

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20011105

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20011106

Year of fee payment: 6

Ref country code: MC

Payment date: 20011106

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20011130

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20011221

Year of fee payment: 6

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20020103

Year of fee payment: 6

26N No opposition filed
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021128

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021128

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021128

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021128

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021129

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021130

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021130

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021231

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20030220

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20030226

Year of fee payment: 7

BECH Be: change of holder

Owner name: *ABBOTT G.M.B.H. & CO. K.G.

Effective date: 20030225

BECN Be: change of holder's name

Owner name: *ABBOTT G.M.B.H. & CO. K.G.

Effective date: 20030225

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: ABBOTT GMBH & CO. KG

Free format text: KNOLL AKTIENGESELLSCHAFT#KNOLLSTRASSE 32#67061 LUDWIGSHAFEN (DE) -TRANSFER TO- ABBOTT GMBH & CO. KG#MAX-PLANCK-RING 2#65205 WIESBADEN (DE)

NLS Nl: assignments of ep-patents

Owner name: KNOLL GMBH

Owner name: ABBOTT GMBH

NLT1 Nl: modifications of names registered in virtue of documents presented to the patent office pursuant to art. 16 a, paragraph 1

Owner name: ABBOTT GMBH & CO. KG

BERE Be: lapsed

Owner name: *ABBOTT G.M.B.H. & CO. K.G.

Effective date: 20021130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030601

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030603

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030609

EUG Se: european patent has lapsed
REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030731

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 20030601

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20030531

Ref country code: FR

Ref legal event code: CD

Ref country code: FR

Ref legal event code: CA

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20031128

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20031129

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20051128

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20031129